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peptide science.
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Temporal Profiles of Natriuretic Peptides and Echocardiographic Indices During Decongestion: Insights from a Cardio-Renal Hemodialysis Model.
Am J Cardiol
Hisao Yoshikawa, Masaki Iwasaki, Katsushi Amemiya +2 more
The temporal behavior of natriuretic peptides and echocardiographic indices during hemodialysis (HD) remains incompletely characterized. We aimed to delineate their dynamic profiles and rank the timing of changes within a single HD session.
Cardiovascular Risk Reduction With Tirzepatide, a Dual GIP/GLP-1 Agonist, in Patients With Type 2 Diabetes Mellitus.
J Lipid Atheroscler
Sakiko Terui, Taichi Minami, Keita Nakamura +1 more
Tirzepatide is the first dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GLP-1) receptor agonist to be approved for the treatment of diabetes mellitus. The SURPASS trials investigated the efficacy and safety of tirzepatide, both as monotherapy and as add-on therapy, in comparison with placebo, basal insulin, semaglutide, or dulaglutide in patients with type 2 diabetes. Tirzepatide at doses of 5 mg, 10 mg, or 15 mg produced significant reductions in hemoglobin A1c levels (-1.87% to -2.58%) and body weight (-6.2 to -12.9 kg) in patients with type 2 diabetes, without increasing the risk of serious hypoglycemia. Tirzepatide also improved lipid parameters and lowered blood pressure. Most of the observed adverse events were mild gastrointestinal symptoms, and the occurrence rate of these events was comparable to that associated with GLP-1 receptor agonists such as semaglutide (1 mg) or dulaglutide (0.75 mg). In this review, we summarize the pharmacodynamics and pharmacokinetics of tirzepatide, review the findings from the phase III SURPASS clinical trials, and discuss the anticipated beneficial effects of tirzepatide on the prevention and management of atherosclerosis and dyslipidemia in patients with type 2 diabetes mellitus.
Comparative Efficacy and Safety of Tirzepatide versus Semaglutide: A Systematic Review and Meta-Analysis with Cardiometabolic Implications.
Nepal J Epidemiol
Azhar Hafiz Baba, Rameez Akhtar, Anurag Rawat +8 more
Obesity and type 2 diabetes are significant global health problems. Tirzepatide, a dual GIP/GLP-1 receptor agonist, and semaglutide, a selective GLP-1 receptor agonist, are the top incretin therapy options, but their relative effectiveness and safety based on direct head- to -head studies have not been pooled. This meta-analysis aims to compare the efficacy and safety of tirzepatide versus semaglutide.
DNA-based delivery of incretin receptor agonists using MYO Technology leads to durable weight loss in a diet-induced obesity model.
Mol Ther Nucleic Acids
Linda Sasset, Andrew D Cameron, Carleigh Sussman +8 more
Incretin receptor agonists (IRAs) have recently come to prominence as powerful weight and glucose control drugs and are approved for the treatment of type 2 diabetes (T2D) and obesity. Semaglutide and tirzepatide, currently the most widely prescribed within this class, are both potent molecules but have a short half-life, requiring weekly dosing. This requirement can negatively affect quality of life and the adherence to therapy, as well as create a significant financial burden for patients who may have a life-long need for treatment. The MYO Technology platform was developed to overcome these barriers. It consists of therapeutic-encoding plasmid DNA, and a proprietary medical device for intramuscular injection and in vivo electroporation of muscle cells. This leads to the uptake of injected DNA, expression of the therapeutic, and its secretion into peripheral circulation. Here, we demonstrate that MYO Technology-delivered IRAs are efficacious in promoting long-lasting weight and glucose control in mouse models of diet-induced obesity. Moreover, engineering the IRAs to facilitate blood-brain barrier penetration further enhances treatment efficacy, with benefits persisting beyond 1 year following a single administration. Together, these findings highlight MYO Technology's potential to transform standard of care by enabling long-lasting therapeutic effects with minimal dosing.
GLPs Significantly Decrease the Risk of Postoperative Surgical Complications: A TriNetX Retrospective Cohort Study.
Dermatol Surg
Marie Vu, Madelyn Schmidt, Smiti Gandhi +1 more
Glucagon-like peptide-1 (GLP) receptor agonists have demonstrated anti-inflammatory and wound-healing properties, but their impact on outcomes after dermatologic surgery has not been evaluated.
Cutaneous Variations in Stem-Cell Population in Those on GLP1-Receptor Agonists: A Comparative Controlled Study.
Dermatol Surg
Maya Firsowicz, Payvand Kamrani, Raheel Zubair +3 more
Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with cutaneous changes including accelerated skin aging and volume loss. The biological mechanisms underlying these effects remain poorly understood, with limited in vivo human data.
A cross-talk between p16High senescence and cellular reprogramming.
Clin Sci (Lond)
Alexander Emelyanov, Dmitry V Bulavin
Cellular senescence and OSKM (Oct4, Sox2, Klf4, and Myc)-mediated reprogramming represent interconnected biological programs that both play important roles in regulating cellular plasticity. Recent studies have highlighted the role of p16-driven senescence in establishing a stable barrier to reprogramming by limiting epigenetic flexibility. Mechanistically, p16High senescent fibroblasts enforce this barrier through stress-induced and AP-1-driven epigenetic remodeling and NNMT-mediated metabolic SAM depletion, which restricts methylation-dependent chromatin remodeling in both p16High and neighboring p16Low cells via a paracrine mechanism. Conversely, clearance of p16High cells restores SAM levels and enhances cellular plasticity in neighboring cells, enabling the acquisition of totipotent-like states during reprogramming. Within p16High cells themselves, reprogramming can reverse some features of senescence, restoring more youthful cellular states under controlled conditions. Importantly, p16High cells remain highly resistant to full reprogramming, minimizing the risk of teratoma and tumor formation in vivo and making them promising target for rejuvenation strategies based on partial reprogramming. In this review, we examine the molecular interplay between p16High senescence and reprogramming, highlighting their dual roles as both barriers to and facilitators of cell fate transitions.
Sex-Biased Pharmacotherapeutic Disparities in Hypertension.
Drugs
Serge Yaacoub, Charles Bardawil, Ryan Yammine +2 more
Hypertension manifests with striking sex-based disparities in prevalence, pathophysiology, and therapeutic outcomes, necessitating the reappraisal of current management paradigms. For example, men exhibit higher blood pressure (BP) in early adulthood, while post-menopausal women suffer from accelerated cardiovascular risk owing to estrogen depletion, endothelial dysfunction, and distinct aging trajectories. Moreover, the renin-angiotensin-aldosterone system (RAAS) operates rather divergently: testosterone upregulates vasoconstrictive angiotensin II type 1 receptors in men, whereas estrogen enhances nitric oxide bioavailability and modulates angiotensin II type 2 receptor in premenopausal women. These hormonal influences extend to cardiovascular aging, as women develop greater arterial stiffness post-menopause, predisposing them to heart failure with preserved ejection fraction. Conversely, men demonstrate higher endothelial dysfunction and cardiomyocyte apoptosis. Furthermore, sex-specific pharmacokinetic profiles (e.g., renal clearance, hepatic metabolism) and pharmacodynamic responses to antihypertensives underscore the inadequacy of uniform treatment strategies. This is demonstrated in women by the observed reduced efficacy of angiotensin-converting enzymes inhibitors, but superior blood pressure control using diuretics. Men, however, respond more robustly to beta blockers. Emerging evidence highlights epigenetic modifiers, including X-chromosome-linked microRNAs (miRNAs) and sex-hormone-driven transcriptional regulators, as pivotal mediators of vascular tone and drug metabolism disparities. Despite these insights, clinical guidelines remain relatively inadequately stratified by sex, perpetuating suboptimal outcomes. This review synthesizes molecular, physiologic, and pharmacotherapeutic axes of sexual dimorphism in hypertension. It also advocates for precision medicine approaches that integrate hormonal status, aging-related vascular remodeling, and genetic polymorphisms. Addressing these physiological paradigms promises to bridge the translational gap between bench and bedside, ultimately mitigating the global burden of hypertensive disease, while mitigating shortcomings in sex-based antihypertensive management.
Associations of PYY, GLP-1 and LEAP2 with changes in feeding-related cognition, body weight and glucose homeostasis after bariatric surgery in non-diabetic women.
J Neuroendocrinol
María F Andreoli, Pablo N De Francesco, Wei Zhou +6 more
Roux-en-Y gastric bypass (RYGB) is an effective surgical intervention for severe obesity, but the role of gastrointestinal hormones in its benefits remains unclear. We examined longitudinal pre-to-post-meal gastrointestinal hormone changes and their relationships with glucose homeostasis and feeding-related cognitive responses in women undergoing RYGB. Seventeen non-diabetic women were evaluated pre-RYGB (Visit 1, V1), 1-month post-RYGB (Visit 2, V2), and 1-year post-RYGB (Visit 3, V3). Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), ghrelin, and liver-expressed antimicrobial peptide 2 (LEAP2) were measured before and after a breakfast in all visits. Appetite ratings and feeding-related cognitive performance were evaluated using visual analog scales, Ideal Portion Size, and Food Stroop tasks. At V3, RYGB induced weight loss (30.8%) and improved glucose homeostasis (p = .020), accompanied by reduced hunger (p = .042), smaller self-reported ideal portion size (p < .001), and improved cognitive control toward food-cues (p = .002). Fasting GLP-1 and PYY levels remained stable across visits but showed enhanced post-meal responses at V2 and V3 (GLP-1: p < .001; PYY: p = .013). Ghrelin levels increased post-RYGB (p = .010) without post-meal variation. LEAP2 concentrations remained stable. Fasting LEAP2 correlated positively with BMI at V1 (p < .001). Fasting PYY correlated inversely with BMI at V3 (p = .005), and its post-meal rise inversely correlated with ideal portion size at V1 (p = .022). GLP-1 increments negatively correlated with ideal portion size (p = .007) at all visits and glycemia (p = .017) at V1. In non-diabetic women, RYGB improves feeding-related cognitive processes. BMI is associated with LEAP2 only pre-surgery, and with PYY 1-year post-RYGB. Restoration of GLP-1 and PYY post-meal increments contributes to metabolic and behavioral improvements. Clinical Trial Registry: This study was registered at clinicaltrials.gov as NCT01815216. https://clinicaltrials.gov/study/NCT01815216.
Targeting Inflammation and Fibrosis in Lipedema: The Potential Role of Glucagon-like Peptide-1 Receptor Agonist Therapies.
Dermatol Surg
Yasmine Mohseni, Aria Vazirnia, Ardalan Minokadeh +2 more
Lipedema is a chronic disorder characterized by disproportionate accumulation of subcutaneous fat, most commonly affecting the extremities, and is associated with pain, inflammation, and fibrosis. Effective medical therapies are lacking, and liposuction remains the primary treatment. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate metabolic and anti-inflammatory effects, but their role in lipedema remains unclear.
Baseline serum cortisol as a prognostic biomarker for immune checkpoint inhibitor therapy in advanced gastric cancer.
Front Oncol
Yufei Zhao, Zhanjun Guo, Jingjing Zhang +1 more
Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced gastric cancer (AGC), but only a subset of patients benefit. Validated prognostic biomarkers for ICI efficacy in AGC remain limited, and the role of endogenous cortisol-an immunosuppressive steroid hormone-in modulating ICI response is unclear.
Sex-specific molecular and cellular phenotypes during resolution of neuropathic pain in dorsal root ganglia.
Cell Rep
Felicitas Schlott, Beate Hartmannsberger, Thorsten Bischler +5 more
The dorsal root ganglion (DRG) is examined for sex-dependent phenotypes in sensory neurons, satellite glial cells (SGCs), and local macrophages following traumatic nerve injury and during natural pain resolution. Systematic analysis of 7,495 DRG immunofluorescence images and 62 transcriptomes reveals pronounced sex-specific, multicellular DRG phenotypes, particularly during pain resolution. Tissue size and neuron density also show sex-dependent differences. Neuropathic pain is resolved without tissue or sensory neuron loss. After injury, macrophages localize to the space between sensory neurons and SGCs; this effect is partially reversed during pain resolution, particularly in males. In females, immune-related gene expression and macrophage phenotypes persist longer, while SGC activation and contact with sensory neurons are more persistent in males. During resolution, synaptic and excitability-related processes are marked in both sexes. In summary, injury responses were largely shared between sexes, whereas the resolution phase exhibited distinctly sex-specific molecular and cellular signatures.
Visualizing a lung neutrophil-platelet immunothrombosis cascade during sepsis in mice.
Science
Luke Brown, Jared Schlechte, Mahum Rashid +8 more
Sepsis is an immune paradox in which host defense is necessary for survival but also contributes to organ damage and death. We defined an immunothrombosis cascade of neutrophil and platelets in the lung microcirculation of Escherichia coli-septic mice. Cathelicidin, an antimicrobial peptide, localized neutrophils to E. coli and initiated immunothrombi through formyl-peptide receptors. Immunothrombi captured bacteria, and cathelicidin enabled antimicrobial activities in platelets. Blocking cathelicidin prevented immunothrombosis and attenuated early sepsis death but resulted in delayed death with uncontrolled infection. Leukotriene B4, an important neutrophil-to-neutrophil communication molecule, amplified immunothrombi, and inhibiting it improved vascular compromise while preserving host defense, thus representing a discrete inflection point of sepsis disease progression. Therefore, targeting the immunothrombi cascade can mitigate immunopathology without suppressing host defense during sepsis.
Comparative Effectiveness of CagriSegma, Semaglutide, Cagrilintide and Tirzepatide in the Management of Overweight and Obesity: A Network Meta-Analysis of Randomized Clinical Trials.
Endocrinol Diabetes Metab
Sultan Hamarsheh, Abdel Rahman Jaber, Omar Abu-Khazneh +4 more
Obesity is a chronic, progressive disease affecting over 1 billion adults worldwide, linked to serious comorbidities, including diabetes, hypertension, and cardiovascular disease and associated with increased mortality. Achieving clinically meaningful weight loss is critical to reducing cardiometabolic risk. Tirzepatide, semaglutide, cagrilintide and their combination (CagriSema) have demonstrated efficacy in clinical trials; however, no direct head-to-head studies have compared all advanced anti-obesity medications. This network meta-analysis examines their comparative efficacy and safety.
Safety, tolerability and efficacy of GLP-1 receptor agonists (GLP-1 RA) in the management of post-liver transplant weight gain: A multicenter, observational study.
Liver Transpl
Mohammad Qasim Khan, Chiara Becchetti, Mahmoud Riyam Jouid +13 more
Post-liver transplant (LT) weight gain and metabolic dysfunction predispose to cardiovascular (CV) morbidity, allograft steatosis, and reduced long-term survival. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) promote weight loss and improve cardiometabolic health, yet evidence in liver transplant recipients (LTR) is limited. We aimed to evaluate the safety, tolerability, and efficacy of GLP-1 RAs in post-LT weight management.
Comparative Effects of Individual Glucagon-Like Peptide-1 Receptor Agonist-Based Medications on Direct Measurement of Body Composition Among Adults With Overweight or Obesity With or Without Type 2 Diabetes: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials.
Diabetes Obes Metab
Nuttaya Wachiraphansakul, Thanawat Vongchaiudomchoke, Worapaka Manosroi +7 more
To compare the effects of individual glucagon-like peptide-1 receptor agonists (GLP-1RAs) on direct body composition among adults with overweight or obesity, with or without type 2 diabetes (T2D).
Beyond weight loss: multisystem benefits of obesity medications.
Lancet Diabetes Endocrinol
Mesut Savas, Susanne Kuckuck, Mariëtte R Boon +1 more
Obesity is increasingly managed with medications as disease-modifying therapies, reflecting its role as a gateway disease driving metabolic, cardiovascular, reproductive, neuropsychiatric, and mechanical conditions. This Review synthesises evidence from randomised controlled trials and high-quality meta-analyses on approved and late-stage investigational obesity medications, including phentermine-topiramate, naltrexone-bupropion, glucagon-like peptide-1 (GLP-1) receptor agonists (eg, liraglutide, semaglutide, subcutaneously and orally), and newer GLP-1 receptor agonist-based agents (eg, tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). We evaluated the effects of obesity medications across major obesity-related conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnoea syndrome, polycystic ovary syndrome (recently named polyendocrine metabolic ovarian syndrome), osteoarthritis, muscle mass, depression, quality of life, and food cravings, along with binge-eating disorders, substance use disorders, and neurodegenerative diseases. Overall, GLP-1-based and multiagonist therapies show beneficial effects across these comorbid conditions. While many benefits of obesity medications are mediated by weight loss, accumulating evidence indicates important weight loss-independent effects, particularly with GLP-1 receptor agonist-based therapies. A broader understanding of these pleiotropic effects is essential to inform personalised obesity management and optimise long-term clinical outcomes.
Molecular Imaging of Butyrylcholinesterase Associated with Amyloid-β Plaques Distinguishes 5XFAD from Wild-Type Mice: A Proof-of-Concept.
Mol Imaging Biol
G Andrew Reid, Drew R DeBay, Ian R Macdonald +3 more
Diagnosis of Alzheimer's disease (AD) requires symptoms of dementia and accumulation of amyloid-β (Aβ) and tau in the brain. Molecular imaging of Aβ or tau in AD, though informative, is complicated by the finding that similar changes are found in brains of ~ 30% of cognitively normal older individuals. Butyrylcholinesterase (BChE), normally present in low levels in the cerebral cortex, is found in high levels associated with Aβ plaques in AD. When associated with plaques, the biochemical properties of BChE are altered. The aim of the present study was to determine if the BChE ligand, [18F]1-methyl-4-piperidinyl p-fluorobenzoate ([18F]BMP), can image BChE-associated plaques in the 5XFAD mouse model of AD and distinguish it from its wild-type (WT) counterpart.
Dynamic degradation and glycoform heterogeneity of NT-proBNP in serum: Implications for biomarker quantification.
Int J Biol Macromol
Junyi Wu, Xueting Ma, Yajing Dong +4 more
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a widely used biomarker for heart failure, yet its circulating molecular heterogeneity and susceptibility to ex vivo proteolysis complicate accurate and traceable quantification. In this study, we systematically investigated the degradation behavior of NT-proBNP in human serum and identified kinetically stable endogenous glycoforms using immunoaffinity enrichment coupled with MALDI-TOF mass spectrometry. Non-glycosylated recombinant NT-proBNP spiked into serum underwent rapid proteolytic processing, dominated by stepwise C-terminal truncation, with extensive fragmentation observed within hours even at 4 °C. Protease inhibition experiments performed under accelerated incubation conditions (37 °C, up to 48 h) confirmed that these changes were enzyme-driven. Against this dynamic background, two NT-proBNP-related peaks at m/z 9084 and 9517 remained qualitatively detectable throughout the entire incubation series, whereas labile non-glycosylated forms showed rapid attenuation. These peaks were reproducibly detected in the small NT-proBNP-positive sample set and were not detected in the small NT-proBNP-negative comparison set, supporting preliminary analytical specificity in this pilot dataset. Mass-balance modeling suggested that both species may correspond to proteolytically processed NT-proBNP backbones carrying clustered mucin-type O-glycosylation involving GalNAc, hexose, and sialic acid residues; these assignments should be regarded as putative compositions requiring orthogonal structural validation. Together, these results suggest that O-glycosylation may contribute to the qualitative persistence of specific NT-proBNP-related species in serum. The m/z 9084 and 9517 peaks should therefore be regarded as candidate, analytically persistent signals detected under the present 15F11-based immunoenrichment and MALDI-TOF MS workflow. Their potential use as robust analytical targets or anchors remains a hypothesis that will require orthogonal structural confirmation, quantitative validation, and evaluation in larger cohorts.
GIP in Cardiovascular and Kidney Disease: From Physiology to Pharmacology.
Diabetes Obes Metab
Michelantonio De Fano, Line L Haurum, Christine R Schwarz +2 more
To provide a comprehensive overview of the cardiovascular and renal effects of glucose-dependent insulinotropic polypeptide (GIP) by integrating its physiological role with recent human trial data on tirzepatide, the first dual GIP and glucagon-like peptide-1 (GLP-1) receptor agonist.